Contact PD/PI: Whistler, Jennifer Summary. Alleviating anxiety and depression is pivotal for reducing the risk of relapse in alcoholics. Currently available anxiolytic and anti-depressant treatments have limited utility in alcohol use disorders (AUDs) due to their reduced efficacy in alcohol dependent subjects. Consequently there is a great need to identify new targets for intervention in anxiety and depression, in particular for use in treatment-seeking alcoholics to manage these comorbidities. Neuropeptide S (NPS) and its receptor (NPSR) comprise a recently de-orphanized G protein- coupled receptor (GPCR) system that has been implicated in stress and anxiety. Activation of the NPSR produces anxiolytic and anti-depressant effects without sedation. In humans, there are two allelic variants of the NPSR that occur at almost equal frequency: I107, the wild type allele, and N107, a mutant variant. Importantly, genome wide analysis studies have demonstrated that variation at this locus is linked to risk of anxiety disorders, as well as anxiety sensitivity in the context of stressful environmental states. In addition, very recently, the mutation at this locus has been linked to AUDs. These data suggest that variation in the NPSR could influence risk for AUDs, in particular risk for anxiety and depression in abstinence during treatment. We have recently reported that NPS can reduce ethanol consumption at doses that are not innately either rewarding or aversive. Importantly we have also found that the anxiolytic and anti-depressant effects of NPS are maintained in mice that have been consuming ethanol, unlike classic anxiolytic and antidepressants. Together these data suggest that the NPSR could be a viable target for intervention in AUDs. Here we propose to generate mice with the mutation allele of the NPSR. We will then use these mice to examine whether allelic variation in the NPSR alters risk for AUDs by affecting ethanol consumption, ethanol reinforcement, baseline anxiety and/or depression as well as anxiety and depression during withdrawal. Taken together, the studies here will further validate the NPSR for intervention in AUDs, and could also provide novel insight as to whether variation at this locus could contribute to genetic risk for AUDs. Project Summary/Abstract Page 6